Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Cup-like blasts in acute myeloid leukemia.

A patient with AML with normal karyotype and the cytological pattern of cup-like blasts (CLB) is reported. The typical morphology on Pappenheim stained blood smears is shown. In addition transmission electron microscopy pictures demonstrate impressively the invaginated nuclear pocket compressing the chromatin. Cup-like blasts usually do not express CD34. There is a close relationship of CLB-AML with the molecular aberrations of NPM1 and/or FLT3-ITD.

Novel homozygous nonsense mutation in the P5'N-1 coding gene as an alternative cause for hereditary anemia with basophilic stippling.

Hereditary pyrimidine 5-nucleotidase (P5'N-1) deficiency is a very rare disorder. Here, we describe a new mutation in a Turkish family. Although functional tests have not been performed, our findings confirm that the homozygous mutational state leads to clinical manifest P5'N-1 deficiency, while heterozygosity does not lead to hemolysis or anemia.

Safe use of FOLFOX in two patients with metastatic colorectal carcinoma and severe hepatic dysfunction.

BACKGROUND: Chemotherapeutic options for patients with metastasised colorectal cancer and impaired liver function are limited. Although oxaliplatin and 5-FU are well tolerated as single therapeutic agents, data supporting their use as combination chemotherapy in the setting of severe hepatic dysfunction are insufficient. PATIENTS AND METHODS: Here, we report on 2 patients with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. On admission both patients displayed a bilirubin of > 22 mg/dL and an alkaline phosphatase (AP) of > 350 U/L as signs of extensive hepatic tumor spread. We initiated a 5-FU/oxaliplatin-based combination chemotherapy in both patients. RESULTS: Liver function and clinical performance improved dramatically within the first cycles of therapy in both patients. On radiologic evaluation, we observed 1 partial response and one long-term (10 months) disease stabilization. The toxicity was acceptable in both patients. CONCLUSION: We concluded that oxaliplatin-based combination chemotherapies (eg FOLFOX4) may achieve good tumor response without significant side effects in patients with metastatic colorectal cancer and hepatic dysfunction.

Equitoxicity of bolus and infusional etoposide: results of a multicenter randomised trial of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL) in elderly patients with refractory or relapsing aggressive non-Hodgkin lymphoma using the CEMP regimen (cisplatinum, etoposide, mitoxantrone and prednisone).

To compare toxicity of etoposide bolus with continuous infusion and to assess the efficacy of the CEMP (cisplatinum, etoposide, mitoxantrone, prednisone) regimen, 47 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma older than 60 years (n=43) or not qualifying for high-dose chemotherapy (n=4) received five four-weekly CEMP cycles. Patients were randomised to start with bolus or continuous-infusion etoposide and then received bolus and infusional etoposide in an alternating fashion. The primary objective was the comparison of differences in the course of leukocytopenia and thrombocytopenia between the two application schedules. CEMP was well tolerated with little organ and moderate haematotoxicity. There was no difference in toxicity between bolus and continuous-infusion etoposide. Complete remission rate was 44% in patients relapsing >or=1 year, 27% in patients relapsing within the first year after achieving complete remission and 5% in primary refractory patients. Median event-free and overall survivals for all patients were 3 and 10 months, respectively. The observed equitoxicity and the more challenging logistics of a 60-h infusion make bolus injection the preferred application of etoposide. As the CEMP regimen is well tolerated and efficacious in elderly patients with relapsed or refractory aggressive non-Hodgkin's lymphoma for whom more aggressive therapies are not feasible, a three-weekly modification of CEMP should be tested in combination with rituximab.

Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.

Phase 2 studies suggest that the monoclonal antibody rituximab may improve the prognosis of patients with follicular lymphoma (FL) when it is added to chemotherapy. In the current study, 428 patients with untreated, advanced-stage FL were randomly assigned for therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone (n = 205) or CHOP combined with rituximab (R-CHOP) (n = 223). R-CHOP reduced the relative risk for treatment failure by 60% and significantly prolonged the time to treatment failure (P < .001). In addition, a significantly higher overall response rate (96% vs 90%; P = .011) and a prolonged duration of remission (P = .001) were achieved. In spite of a relatively short observation time, these beneficial effects even translated to superior overall survival (P = .016), with 6 deaths in the R-CHOP group compared with 17 deaths in the CHOP group within the first 3 years. The predominant treatment-related adverse effect was myelosuppression. Severe granulocytopenia was more frequently observed after R-CHOP (63% vs 53%; P = .01). However, severe infections were rare and of similar frequency after R-CHOP and CHOP (5% and 7%). Hence, adding rituximab to CHOP significantly improves the outcome for patients with previously untreated advanced-stage FL and does not induce major adverse effects.